Skip Navigation LinksHome > February 2014 - Volume 9 - Issue 2 > Incorporating Immune-Checkpoint Inhibitors into Systemic The...
Journal of Thoracic Oncology:
doi: 10.1097/JTO.0000000000000074
State of the Art: Concise Review

Incorporating Immune-Checkpoint Inhibitors into Systemic Therapy of NSCLC

Champiat, Stéphane MD*; Ileana, Ecaterina MD; Giaccone, Giuseppe MD, PhD; Besse, Benjamin MD, PhD§; Mountzios, Giannis MD, PhD; Eggermont, Alexander MD, PhD; Soria, Jean-Charles MD, PhD

Free Access
Article Outline
Collapse Box

Author Information

*SITEP (Service d’Innovations Therapeutiques Precoces), Department of Medicine, Gustave Roussy, Institut Gustave Roussy, University Paris Sud, Villejuif, France; Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia; §Thoracic Multidisciplinary Committee, Gustave Roussy, University Paris Sud, Villejuif, France; and Department of Medical Oncology, University of Athens School of Medicine, Athens, Greece.

Disclosure: Dr. Eggermont has received consulting fee or honorarium from BMS, GSK, MedImmune, and MSD. Dr. Soria has received consulting fee or honorarium from Genentech. Drs. Champiat, Ileana, Giaccone, Besse, and Mountzios declare no conflict of interest.

Address for correspondence: Stéphane Champiat, MD, Institut Gustave Roussy 114 rue Édouard-Vaillant, Villejuif 94800, France. E-mail:

Collapse Box


Despite current therapeutic options metastatic non– small-cell lung cancer (NSCLC) remains incurable. Targeted therapies have opened new opportunities for several molecular subtypes, but virtually all patients treated will ultimately develop progressive disease by treatment resistance. Recent clinical trials have shown that immune-checkpoint blockade can result in striking and durable responses in metastatic NSCLC. These impressive results are yet to be confirmed in following trials; nonetheless, NSCLC therapeutic strategies will most likely need to integrate immune-checkpoint inhibitors in the near future. Interestingly, conventional therapies are capable of modulating the immune system and can therefore interact directly or indirectly with immunotherapies. This suggests that some combinations might have synergistic activity and lead to improved efficacy. Conventional and targeted therapies can induce rapid tumor lysis, and immune-checkpoint blockade can then help to induce a sustained immune-mediated tumor control. Moreover, the distinctive toxicity profile associated with immune-checkpoint modulators makes them good candidates for combination strategies. Here we summarize the results of immune-checkpoints trials in NSCLC, and also report how current therapeutic options can modulate the immune system. We provide a rationale and identify potential challenges for immune-checkpoint blockade combinations with conventional therapeutics in NSCLC.

Back to Top | Article Outline


Non–small-cell lung cancer (NSCLC) accounts for 85% of lung cancer, and 70% of NSCLC patients present with locally advanced or metastatic disease at the time of diagnosis. Unfortunately, metastatic lung cancer is incurable with the current therapeutic options. Platinum-based doublet chemotherapy remains the standard first-line treatment for advanced and metastatic NSCLC. These combination regimens have shown to prolong survival and improve quality of life, however, their toxicity profile limits their use to patients with good performance status. In metastatic NSCLC several regimens have shown comparable efficacy with different toxicity profiles that are taken into account for treatment selection. Targeted agents are now among the therapeutic options for patients with NSCLC and specific oncogenic characteristics. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors attain high response rates in patients with tumors with activating EGFR mutations. Crizotinib also achieve high response rates in anaplastic lymphoma kinase (ALK)-translocated and ROS1-translocated NSCLC patients.

More recently, promising results have been reported with immune-checkpoint blockers (targeting cytotoxic T-lymphocyte–associated antigen 4 [CTLA4], programmed death 1 protein [PD-1] or PD-L1) in advanced NSCLC with objective responses in around 20% of patients. Clinical results obtained with immune-checkpoint inhibitors illustrate how immunotherapy can induce long-lasting disease control. However, one of the major weaknesses of immunomodulators is the limited proportion of responders. This could partially be because of the immunosuppressive potential of tumor cells and their environment. Intriguingly, many of the activated pathways in NSCLC are also involved in the development, activation, and function of the immune response.

NSCLC conventional therapies are capable of modulating the immune system. They can potentially interact directly or indirectly with immunotherapies and this suggests that their combination might have synergistic activity and lead to improved efficacy. Moreover, immune-checkpoint modulators have a different toxicity profile that makes them good candidates for combination strategies. Conventional and targeted therapies can help to obtain rapid tumor regressions, and immune-checkpoint blockade can then help to consolidate the response by inducing a long-lasting immune-mediated tumor control (Fig. 1).

Figure 1
Figure 1
Image Tools

This review will illustrate the role of the immune system in NSCLC and the results of immune-checkpoint blockade. We will detail the molecular pathways underlying T cell activation and describe how immune checkpoints can be modulated by NSCLC conventional therapies. We will then focus on the rationale for combination strategies and the potential challenges that may be encountered.

Back to Top | Article Outline
Immune Checkpoints and Their Blockade in NSCLC

As illustrated in Figure 2, different phases are required to develop efficient antitumor immune responses in NSCLC. After antigen recognition by the T cell receptor, T cell activation is regulated by a balance between costimulatory and inhibitory signals. These inhibitory signals are mediated by immune checkpoints: they are membrane receptors and ligands that play a key role in maintaining self-tolerance by modulating duration and amplitude of immune responses.1 Tumors are able to divert the immune-checkpoint pathways to avoid immune destruction.1 Therefore, the blockade of immune checkpoint seems to be crucial for the activation of effective antitumor immune responses.

Figure 2
Figure 2
Image Tools
Back to Top | Article Outline
Cytotoxic T-Lymphocyte–Associated Antigen 4

CTLA4 is expressed exclusively on T cells where it primarily regulates the amplitude of the early stages of T cell activation (priming). It counteracts the activity of the T cell costimulatory receptor, CD28. CD28 and CTLA4 share identical ligands: CD80 (also known as B7.1) and CD86 (also known as B7.2), and CTLA4 has a much higher overall affinity for both ligands. Anti-CTLA4 antibodies are the first immune-checkpoint inhibitors that have been developed and approved by the Food and Drug Administration in 2011 for advanced and metastatic melanoma.

Ipilimumab in combination with chemotherapy has shown promising results in patients with NSCLC. A phase II randomized trial studied ipilimumab in combination with paclitaxel and carboplatin versus chemotherapy alone in two different schedules (phased or concurrent).2 The primary endpoint of the study was an improvement of the immune-related progression-free survival (ir-PFS).3 Two hundred and four chemotherapy-naive patients with advanced NSCLC were included and treated with paclitaxel (175 mg/m2) and carboplatin (area under the curve 6) once every 3 weeks plus ipilimumab (10 mg/kg) or placebo. The concurrent arm consisted of ipilimumab given concurrently for four doses followed by placebo. The phased arm consisted of two doses of placebo followed by four doses of ipilimumab. After six cycles of the combination, placebo or ipilimumab was given every 12 weeks until disease progression. The ir-PFS was improved in patients receiving the phased schedule versus chemotherapy alone (HR, 0.72; P = .05). The concurrent schedule did not improve the ir-PFS. The median irPFS was 5.68 months for the phased arm versus 4.63 months for chemotherapy alone (hazard ratio [HR] = 0.68, p = 0.026) and was 5.52 months for the concurrent arm versus 4.63 months for chemotherapy alone (HR = 0.77, p = 0.094). Overall survival (OS) was improved in the phased-schedule group (12.2 months median OS) compared with the chemotherapy-alone arm (8.3 months), but this gain was not statistically different (p = 0.104).

Back to Top | Article Outline
Anti–PD-1/PD-L1 Monoclonal Antibodies

The PD-1 is another key immune-checkpoint receptor expressed by activated T cells.1 Compared with CTLA4, PD-1 modulates a later stage of the immune response. Instead of affecting the initial stage of T-cell activation (priming) in the regional lymph node, PD-1 regulates the activation of T cells in peripheral tissues. Like CTLA4, PD-1 can be found on the surface of the activated TReg lymphocytes and also on B lymphocytes or natural killer cells. PD-1 binds to its ligands PD1-L1 (B7-H1) and PD1-L2 (B7-DC), which are expressed on antigen presenting cells but also on cancer cells. Indeed, one important mechanism for tumor cells to escape the immune system is by overexpressing PD-1 ligands on their surface. Expression of immune-checkpoint ligands can be innate through constitutive oncogenic signaling or induced in response to inflammatory signals (IFN-g) that are produced by an active antitumor immune response. PD-L1 expression was described in many histological cancer types and in particular in lung cancer where approximately 50% of NSCLCs are reported to express PD-L1.4,5

Monoclonal antibodies targeting both PD-1 and PD-L1 are being developed, which have demonstrated significant clinical activity against several tumor types (Table 1). Nivolumab (BMS-936558) is a fully humanized antibody that targets the PD-1 receptor, preventing its activation by PD-L1 or PD-L2. A phase I trial tested nivolumab in 296 patients with advanced solid cancers, including 129 NSCLC patients.6,7 Nivolumab was administered intravenously once every 2 weeks at doses of 1, 3 or 10 mg/kg, with 8-weekly cycles. The majority of patients were heavily pretreated (54% of NSCLC patients had already received 3 lines of chemotherapy). Previous treatment included platinum-based chemotherapy (99%) and tyrosine kinase inhibitors (28%). Of the 129 NSCLC patients, 17% had objective responses (n=22). Responses in NSCLCs were seen at all dose levels, but were higher with higher doses: 3% at 1 mg/kg, 24% at 3 mg/kg, and 20% at 10 mg/kg. Objective responses were observed in squamous and nonsquamous NSCLCs: 17% of squamous-cell carcinoma (SCC; n=9 of 54) and 18% of nonsquamous-cell carcinoma (NSCC; n=13 of 74). Median OS (mOS) across all dose cohorts was 9.2 months for SCC and 9.6 months for NSCC. Prolonged responses were reported in both histologies with sustained OS: 44%/41% SCC and 44%/17% NSCC were alive at 1 and 2 years, respectively.

Table 1
Table 1
Image Tools

BMS-936559 (MDX-1105) is a monoclonal antibody that binds to PD-L1, thus preventing its interaction with PD-1. The expansion cohort of its phase I trial included 75 patients with NSCLC.8 Previous treatment included platinum-based chemotherapy (95%), tyrosine kinase inhibitors (41%), and radiation therapy (32%). BMS-936559 was administered intravenously once every 2 weeks at doses of 1, 3, and 10 mg/kg. Forty-nine of the 75 NSCLC patients were evaluable for response and an objective response was seen in five of them at doses of 3 and 10mg/kg. Tumor response was seen in 8% of SCCs (n=1 of 13) and 11% of NSCCs (n=4 of 36). Prolonged disease stabilization was observed: three of the five responders and six additional patients had responses lasting at least 6 months. Although the two trials could not be directly compared, responses seem lower with this PD-L1 antibody compared with nivolumab (anti–PD-1).

MPDL-3280A is a human monoclonal antibody that targets PD-L1, blocking PD-L1 from binding its receptors, including PD-1 and B7.1. In a phase I expansion study, MPDL-3280A was administered intravenously every 3 weeks in patients with locally advanced or metastatic solid tumors at doses between 1 to 20 mg/kg9. Fifty-three NSCLC patients were evaluable for safety, 98% of patients received prior systemic therapy, 89% had prior surgery, and 55% had prior radiotherapy. Forty-one NSCLC patients were evaluable for efficacy and Response Evaluation Criteria in Solid Tumors responses were observed at all dose levels. Rapid and durable responses were observed with an ORR of 22% (9 of 41). The 6 months PFS was 46%.

The interactions of immune-checkpoint receptors and multiple ligands are complex. Therefore, therapeutics blocking receptors may have different effects than compounds blocking ligands. For example, in the PD-1/PD-L1 pathway, in addition to PD-1, PD-L1 exerts an inhibitory signal to T cells through B7.1.10 Targeting PD-1 will only block PD-1 interaction with its two ligands PD-L1 and PD-L2 but not the inhibitory signal mediated through B7.1. Likewise, blocking PD-L1 regulates T-cell activation through PD-1 and B7.1, but leaves the PD-1/PD-L2 interaction intact. Because PD-L2 has been implicated in regulating Th-2–mediated inflammation,11 PD-L1 blocking strategies may also reduce inflammatory toxicity and potentially prevent autoimmunity.12

Table 1 summarizes immune-checkpoint inhibitors currently developed in NSCLC.

Back to Top | Article Outline
Immunomodulatory Effects of NSCLC Conventional Therapies

Several anticancer drugs, including classical chemotherapies and targeted therapies, have been reported to stimulate tumor-specific immune responses.13,14 Nonetheless, the various available reports suffer from lack of strong evidence and need to be confirmed with consistency to be applied in clinical practice.

Back to Top | Article Outline
Immunomodulatory Effects of NSCLC Chemotherapeutic Agents

Different mechanisms are reported to explain how chemotherapies can affect the immune system in NSCLC. First, chemotherapeutics can elicit a vaccine-like effect against the tumor by triggering immunogenic cell death15 or by enhancing T-cell activation through up-regulation of major histocompatibility complex–1 expression (paclitaxel, gemcitabine)16 or dendritic cells (DCs) modulation (taxanes).17 In addition, chemotherapy can affect immunoregulatory cells like regulatory T cells (TRegs) (cisplatin, paclitaxel)18,19 or myeloid-derived suppressor cells (MDSCs; gemcitabine, cisplatin, and docetaxel).19–21

Back to Top | Article Outline
Immunomodulatory Effects of Radiation Therapy

Ionizing irradiation is commonly used in NSCLC. This therapy has demonstrated to have multiple effects on the antitumor immune system.22 Locally, low-dose radiation leads to reduced secretion of inflammatory cytokines by macrophages (TNFa, NO) and induces an immune suppressive environment (IL-10, TGFß).23 High-dose radiation is associated with increased antigen expression and induction of immunogenic cell death.23 Radiation locally can also trigger systemic immune activation and lead to spontaneous regression of tumors or metastases that are outside the radiation field. This phenomenon is called the “abscopal effect.” Likewise, radiation therapy seems to be a good candidate for combination with immune-checkpoint blockade.24,25 A phase I/II trial is currently evaluating the association of ipilimumab with local radiation therapy in different malignancies (NCT01769222).

Back to Top | Article Outline
Immunomodulatory Effects of NSCLC Targeted Therapies

Bevacizumab targets the vascular endothelial growth factor A, which has immunosuppressor activity: it blocks DC maturation and promotes the proliferation of MDSCs.26 Therefore, bevacizumab can potentially have an immunomodulatory effect through the tumor environment. It has been reported to increase DC priming of T cells through stimulation of DC maturation and inhibition of MDSCs.27 In addition, bevacizumab can deplete TRegs and enhance tumor infiltration by lymphocytes. A phase I trial associating bevacizumab with MPDL-3280A (anti PD-L1) is currently ongoing in NSCLC (NCT01633970).

The EGFR tyrosine kinase inhibitor erlotinib has demonstrated dual immunomodulatory effects. It increases class I and class II major histocompatibility complex expression28 but also exerts a significant inhibition on the T-cell proliferation and activation through down-regulation of the c-Raf/ERK cascade and Akt signaling pathway.29

Back to Top | Article Outline
Oncogenic Pathway Modulation of PD-L1 Expression

Immunotherapies and targeted therapies are often comprehended as part of two completely distinct therapy strategies. Nonetheless, immune system modulation relies remarkably on molecular pathways (Fig. 3) and there is now a clear rationale that activated signaling pathways can affect the antitumor immune response. This allows new opportunities for combinatorial strategies of specific targeted therapies with immune-checkpoint blockers.

Figure 3
Figure 3
Image Tools

Oncogenic signaling pathways may be involved in the regulation of PD-L1 expression at the surface of the tumor cell. It has been demonstrated that activation of the PI3k/Akt pathway in glioma, breast and prostate cancers can lead to increased PD-L1 expression.30,31 Experiments in cancer cell lines indicated that treatment with phosphatidylinositol-3-kinase/Akt inhibitors resulted in its down-regulation. In ALK+ T-cell lymphoma, the chimeric oncogenic kinase NPM/ALK has been reported to drive PD-L1 expression through STAT3.32 In melanoma, activation of MAPK in cells resistant to BRAF inhibitors promotes PD-L1 expression that is reversible by MEK and phosphatidylinositol-3-kinase inhibition.33 These findings explain how oncogenic drivers may play a critical role in cancer immune evasion. Moreover, it confirms the importance to understand the relationship between our current NSCLC therapies and their role in tumor immunity and response to immune checkpoint modulators.

Back to Top | Article Outline
Modulation of PD-L1 Expression by Chemotherapeutic Agents

Interestingly, chemotherapeutic drugs also can modulate immune-checkpoint expression. Effects of different chemotherapies on PD-L1 expression were studied on cancer cell lines. Doxorubicin has been reported to down-regulate PD-L1 expression on cancer cell surface, whereas paclitaxel and etoposide increase PD-L1 expression. Other tested drugs such as cisplatin and docetaxel, however, did not have any significant effect on PD-L1 expression.34,35 This suggests that different chemotherapies may have different effects on costimulatory molecules like PD-L1. Therefore, chemotherapies used in NSCLC such as paclitaxel or etoposide may have a major impact on efficacy of immune checkpoint modulators. This also suggests that some strategic drug combinations could potentially be profitable whereas others could be detrimental.

Back to Top | Article Outline
Rationale for Combination

There is a strong rationale to combine immune checkpoints with a number of therapeutics. The first combination trials have just started especially in melanoma and a few trials have been launched also in NSCLCs (Table 2).

Table 2
Table 2
Image Tools

The objectives of these combinations are to optimize different aspects of the immune response: triggering an antitumor immune response that will be enhanced by the immune checkpoint blockade, decreasing the tumor-induced immunosuppression to facilitate the activated immune response, or specifically increase the immune-checkpoint target expression on tumor cells to boost efficacy, as illustrated in Figure 2.

Back to Top | Article Outline
Triggering an Antitumor Immune Response

To respond to immune checkpoint inhibitors, patients must have a previously developed antitumor T-cell response. Vaccination strategies are specifically developed for such purpose. Currently two types of vaccines have been tested against NSCLC in randomized phase III trials36: tumor cell vaccines (Lucanix)37 and antigen-based vaccines (MAGE-A3,38 BLP-25,39 TG4010,40 and CIMAvax EGF).41 To date, vaccine trials in NSCLC have failed but further combination strategies with immune checkpoints could lead to better efficacy.

Back to Top | Article Outline
Increasing Immune Checkpoint Targets Expression on Tumor Cells

Increasing the expression of immune-checkpoint ligand at the tumor cell surface can help to improve efficacy of its specific drug. Paclitaxel and etoposide could be used to increase PD-L1 expression on NSCLC cells to improve tumor elimination by anti–PD-L1 therapies, for example. As we have seen, multiple molecular pathways can lead to overexpression of immune checkpoints. We can also expect in the future that the use of other targeted therapies may help to specifically modulate checkpoint ligand expression.

Back to Top | Article Outline
Decreasing Tumor-Induced Immunosuppression

To facilitate the antitumor immune response activated by immune-checkpoint inhibition, combination with other therapies could help to decrease the tumor-induced immunosuppression. This effect is obtained by the direct cytotoxic activity of the drugs: elimination of tumor cells reduces its immunosuppressive impact. In addition, cisplatin, taxane, gemcitabine, or bevacizumab can help to inhibit the effect of TRegs and MDSCs.

Back to Top | Article Outline
Targeting Drug-Resistant Clones

A major reason for combination is that it may help to eliminate drug-resistant clones. As previously described, NSCLC patients treated by targeted therapies like erlotinib, gefitinib, or bevacizumab ultimately develop drug resistance leading to tumor growth. Drug resistance is often owed to downstream activation of alternative pathways and nevertheless, some of these alternative signaling can potentially lead to up-regulation of immune checkpoints at the surface of the drug-resistant cell. Therefore, combination of a targeted drug with an immune-checkpoint blocker can be possibly used to extend efficacy against drug-resistant mutants and to improve duration of response.

Back to Top | Article Outline
Maximizing Immune Checkpoint Blockade

Preliminary data are suggesting that blocking immune checkpoints at different levels might have a synergistic effect.42 CTLA4 modulates early activation of the T-cell response in the regional lymph node whereas PD-1/PD-L1 affects later activation in the peripheral tissues. Therefore, combination of immune-checkpoint inhibitors may result in a higher frequency of patients with increased tumor burden reduction and longer duration of response.

A phase I trial has evaluated the combination of ipilimumab with nivolumab in advanced melanoma.43 In the concurrent cohort, melanoma patients received nivolumab and ipilimumab concurrently, every 3 weeks for four cycles, followed by nivolumab alone every 3 weeks for four doses. Efficacy data on patients with concurrent therapy seem to exceed clinical activity published with monotherapy with an ORR of 40% (n=21 of 52). One third of the patients (n=16 of 52) had rapid and deep tumor regressions (≥ 80% tumor reduction at 12-week tumor assessment). Observed responses were durable: after 13 months of follow-up, 90% of all responding patients continue to respond. In the sequenced cohort, melanoma patients that previously received ipilimumab were treated with nivolumab every 2 weeks for a maximum of 48 doses. Twenty percent (n=6 of 0) had confirmed objective responses, including patients with rapid and deep responses (13%, n=4 of 30).

With the discovery and understanding of other immune checkpoints, multiple immune checkpoint antibodies are under development and should help in the near future to stimulate more accurately the antitumor immune response for better efficacy.

Back to Top | Article Outline


Defining the Optimal Treatment Combination Sequence: Phased or Concurrent

The immune system stimulation of conventional therapies may increase tumor-specific immunity and therefore enhance efficacy. However, chemotherapies may also decrease the population of immune cells, mediating the response to immunotherapy. This is the reason why the phased sequence has been suggested to avoid immediate deleterious effect of chemotherapy on the immune response. As reported in the phase II randomized trial studying ipilimumab in combination with paclitaxel and carboplatin, the ir-PFS was only improved in patients receiving the phased schedule.2 More trials with different phased or concurrent combinations will be needed to define the best-association strategy.

Back to Top | Article Outline
Managing Toxicities

To date, immune-checkpoint inhibitors present an acceptable safety profile. Occasional severe toxicities are managed with treatment interruption and steroids or other immune suppressor treatments (like anti-TNF).

Back to Top | Article Outline
Anti-CTLA4 Toxicities

During treatment with anti-CTLA4, a unique set of adverse effects may occur, called immune-related adverse events (irAEs).44–46 Patients treated with 3 mg/kg of ipilimumab (Food and Drug Administration–approved dosage) show that 60% to 80% develop irAE of any grade, mostly skin rashes (40%) and diarrhea (30% to 40%). Other irAEs like hypophysitis, hepatitis, pancreatitis, iridocyclitis, lymphadenopathy, neuropathies, and nephritis have also been described. Most irAEs are grade 1 or 2, although some life-threatening irAEs were observed, and approximately 10% to 15% of ipilimumab-treated patients developed grade 3/4 events. These severe irAEs are essentially diarrhea/colitis (5%). Treatment-related deaths associated with irAEs are reported in 2 % of the treated patients.

Back to Top | Article Outline
Anti–PD-1/PD-L1 Toxicities

The frequency of immune-related toxicities from anti–PD-1/anti–PD-L1 treatments are definitely less than that from anti-CTLA4 treatment. To date, their toxicity profiles seem to be grossly similar with the exception of pneumonitis,which seems to be more frequent in anti–PD-1. In all the phase I trials, the maximum-tolerated dose was not reached, and all doses were found to be safe.6,8,47The long-term follow-up of the nivolumab (anti–PD-1) phase I trial in 127 NSCLC patients evaluable for safety shows that common drug-related AEs were decreased appetite (9%), anemia (8%), diarrhea, nausea, and pruritus (7% each).7 The most common grade 3/4 AEs were fatigue, pneumonitis, and elevated transaminase (2% each). Two drug-related deaths from pneumonitis occurred early in the trial. This led to increased monitoring, and no further deaths from pneumonitis were reported.

In the anti–PD-L1 studies no grade 3 to 5 pneumonitis or diarrhea has been reported.8 There seemed to be more infusion reactions with BMS-936559 than the reported data with nivolumab or ipilimumab. The most common treatment-related AEs were fatigue, infusion reactions, and diarrhea. In the MPDL-3280A study, the incidence of all grade 3/4 AEs, regardless of attribution, was 34%, including pericardial effusion (6%), dehydration (4%), dyspnea (4%), and fatigue (4%).9

The lower toxicity profile of anti–PD-1/PD-L1 compared with ipilimumab may have to do with the different level of action of PD-1/PD-L1 versus CTLA4 in the modulation of the immune response. PD-1/PDL-1 checkpoint interaction takes place peripherally, at the tumor site, whereas CTLA4/B7 interaction occurs mostly centrally in the lymphoid organs. Furthermore, anti–PD-L1 antibodies seem to have a more favorable toxicity profile than anti-PD-1 with no pneumonitis. As previously mentioned, targeting PD-L1 rather than targeting PD-1 may leave PD-L2 uninhibited.12 This would enhance preferably Th1-mediated immune responses for anticancer efficacy but also let PD-L2 suppress Th2 immune responses to maintain immune homeostasis in normal tissues, particularly tissues with high levels of PD-L2, like lung tissue.

Back to Top | Article Outline
Toxicity Profile Reported in First Combination Trials

Immune checkpoints have a good tolerance profile and immune-related AEs have few in common with conventional NSCLC therapies. The first combination study of ipilimumab and chemotherapy in NSCLC was generally well tolerated and ipilimumab did not potentiate chemotherapy-related toxicity.2 However, safety results suggest a moderate added toxicity in the arms containing ipilimumab (grade 3–4 AEs were observed in 58% of patients in the concurrent arm and 52% in the phased arm versus 42% in the placebo arm).

A study of nivolumab with platinum-based doublet chemotherapy in chemotherapy-naive NSCLC patients is currently ongoing.48 Nivolumab doses were started at 10 mg/kg intravenously every 3 weeks and given until progression. Platin-doublet was given for four cycles at standard dosing. Forty-three patients were treated with nivolumab + platin-doublet: 12 SCC NSCLCs with gemcitabine/cisplatin (arm A), 15 NSCC NSCLCs with pemetrexed/cisplatin (arm B), and 16 NSCLCs with carboplatin/paclitaxel ( arm C). Interim analysis reports that no dose-limiting toxicities. were seen across arms. Forty-nine percent grade 3 to 4 regimen-related AEs were reported: 25%, 47%, and 69% for arms A, B, and C, respectively. Across arms, specific grade 3 to 4 toxicities reported included: pneumonitis (7%, n=3), rash (5%, n=2), nephritis (2%, n=1), and colitis (2%, n=1). One of the patients presenting grade 3 pneumonitis subsequently died from Aspergillus pneumonia. One patient died of disease progression with unresolved pneumonitis.

In the phase I trial evaluating the combination of ipilimumab with nivolumab in advanced melanoma, the concurrent cohort had a higher rate of toxicities.43 No treatment-related deaths were reported. Grade 3 to 4–related AEs occurred in 53% of concurrent cohort treated patients (n=28 of 53), representing mostly tissue-specific inflammation. The most common AEs were asymptomatic lab abnormalities: elevations of lipase (13%), AST (13%), and ALT (11%). The dose-limiting toxicity was reached at the third dose stage with ipilimumab 3 mg/kg and nivolumab 3 mg/kg (grade 3–4 lipase increase). At the maximum-tolerated dose, grade 3 to 4 related–AEs occurred in 59% of patients and included uveitis/choroiditis, colitis, and reversible lab abnormalities. In the sequenced cohort, grade 3 to 4–related adverse events occurred in 18% of treated patients (n=6 of 3): the most common was asymptomatic elevation of lipase (6%).

Preliminary data from a phase I/II trial show that the combination of nivolumab with a multipeptide vaccine in unresectable melanoma patients is overall well tolerated and that toxicity is similar to nivolumab monotherapy.49 In the ipilimumab-naive cohorts, grade 3 to 4 AEs only occurred in two of 34 treated patients: one presented optic neuritis and the other pneumonitis. Of 56 patients in the ipilimumab refractory cohort, two patients presented grade 3 to 4 rash and one patient developed grade 3 to 4 pneumonitis.

Back to Top | Article Outline


The development of immune-checkpoint blockade in NSCLC is just beginning and some combination strategy trials have already started (Table 2). Multiple combination strategies in other malignancies should support new trials in NSCLC: ipilimumab with local radiation therapy in metastatic melanoma (NCT01689974), ipilimumab with gemcitabine in pancreatic cancer (NCT01473940), nivolumab with sunitinib or pazopanib in renal cell carcinoma (NCT01472081).

Better understanding of relationship between molecular pathways and immune checkpoints is clearly needed to optimize treatment strategies. Moreover, further studies may help to identify NSCLCs predictive subtypes that will better respond to immune-checkpoint blockade. Indeed, PD-L1 tumor expression has been reported to be a predictive marker of anti–PD-L1 therapy response. In the MPDL-3280A phase I trial, PD-L1–positive tumors showed an ORR of 80% and a PD rate of 0% whereas PD-L1–negative tumors showed an ORR of 14% and a PD rate of 61%.9

Use of biomarkers may therefore become crucial before immune-checkpoint inhibitor prescription. Detailed analysis of the impact of the different NSCLC histological and molecular subtypes on immune-checkpoint markers may help to identify subgroups of patients. Trials using sequential biopsies to assess immune checkpoints and tumor-infiltrating lymphocyte characteristics may be necessary to evaluate the impact of different conventional therapies.

The striking responses obtained with immune checkpoints may position them early in the therapeutic sequence, and combination strategies using chemotherapy, radiation therapy, or molecular-targeted agents may become the backbone of metastatic NSCLC treatment strategy. Moreover, given their low-toxicity profile and impressive results there is no reason to limit their therapeutic potential to the metastatic settings. In the future, immune-checkpoint blockade may play a key role as an adjuvant treatment in locally advanced NSCLC and even in resectable disease.

Back to Top | Article Outline


1. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252–264

2. Lynch TJ, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol. 2012;30:2046–2054

3. Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15:7412–7420

4. Chen YB, Mu CY, Huang JA. Clinical significance of programmed death-1 ligand-1 expression in patients with non-small cell lung cancer: a 5-year-follow-up study. Tumori. 2012;98:751–755

5. Mu CY, Huang JA, Chen Y, Chen C, Zhang XG. High expression of PD-L1 in lung cancer may contribute to poor prognosis and tumor cells immune escape through suppressing tumor infiltrating dendritic cells maturation. Med Oncol. 2011;28:682–688

6. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–2454

7. Brahmer JR, et al. 2013 ASCO Annual Meeting. J Clin Oncol. 2013;31(suppl; abstr 8030)

8. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455–2465

9. Spigel et al. 2013 ASCO Annual Meeting. J Clin Oncol. 2013;31(suppl; abstr 8008)

10. Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity. 2007;27:111–122

11. Akbari O, Stock P, Singh AK, et al. PD-L1 and PD-L2 modulate airway inflammation and iNKT-cell-dependent airway hyperreactivity in opposing directions. Mucosal Immunol. 2010;3:81–91

12. Chen DS, Irving BA, Hodi FS. Molecular pathways: next-generation immunotherapy–inhibiting programmed death-ligand 1 and programmed death-1. Clin Cancer Res. 2012;18:6580–6587

13. Galluzzi L, Senovilla L, Zitvogel L, Kroemer G. The secret ally: immunostimulation by anticancer drugs. Nat Rev Drug Discov. 2012;11:215–233

14. Vanneman M, Dranoff G. Combining immunotherapy and targeted therapies in cancer treatment. Nat Rev Cancer. 2012;12:237–251

15. Hannani D, Sistigu A, Kepp O, Galluzzi L, Kroemer G, Zitvogel L. Prerequisites for the antitumor vaccine-like effect of chemotherapy and radiotherapy. Cancer J. 2011;17:351–358

16. Liu WM, Fowler DW, Smith P, Dalgleish AG. Pre-treatment with chemotherapy can enhance the antigenicity and immunogenicity of tumours by promoting adaptive immune responses. Br J Cancer. 2010;102:115–123

17. John J, Ismail M, Riley C, et al. Differential effects of Paclitaxel on dendritic cell function. BMC Immunol. 2010;11:14

18. Zhang L, Dermawan K, Jin M, et al. Differential impairment of regulatory T cells rather than effector T cells by paclitaxel-based chemotherapy. Clin Immunol. 2008;129:219–229

19. Tseng CW, Hung CF, Alvarez RD, et al. Pretreatment with cisplatin enhances E7-specific CD8+ T-Cell-mediated antitumor immunity induced by DNA vaccination. Clin Cancer Res. 2008;14:3185–3192

20. Le HK, Graham L, Cha E, Morales JK, Manjili MH, Bear HD. Gemcitabine directly inhibits myeloid derived suppressor cells in BALB/c mice bearing 4T1 mammary carcinoma and augments expansion of T cells from tumor-bearing mice. Int Immunopharmacol. 2009;9:900–909

21. Kodumudi KN, Woan K, Gilvary DL, Sahakian E, Wei S, Djeu JY. A novel chemoimmunomodulating property of docetaxel: suppression of myeloid-derived suppressor cells in tumor bearers. Clin Cancer Res. 2010;16:4583–4594

22. Rubner Y, Wunderlich R, Rühle PF, et al. How does ionizing irradiation contribute to the induction of anti-tumor immunity? Front Oncol. 2012;2:75

23. Rödel F, Frey B, Gaipl U, et al. Modulation of inflammatory immune reactions by low-dose ionizing radiation: molecular mechanisms and clinical application. Curr Med Chem. 2012;19:1741–1750

24. Dewan MZ, Galloway AE, Kawashima N, et al. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res. 2009;15:5379–5388

25. Zeng J, See AP, Phallen J, et al. Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas. Int J Radiat Oncol Biol Phys. 2013;86:343–349

26. Alfaro C, Suarez N, Gonzalez A, et al. Influence of bevacizumab, sunitinib and sorafenib as single agents or in combination on the inhibitory effects of VEGF on human dendritic cell differentiation from monocytes. Br J Cancer. 2009;100:1111–1119

27. Shrimali RK, Yu Z, Theoret MR, Chinnasamy D, Restifo NP, Rosenberg SA. Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer. Cancer Res. 2010;70:6171–6180

28. Pollack BP, Sapkota B, Cartee TV. Epidermal growth factor receptor inhibition augments the expression of MHC class I and II genes. Clin Cancer Res. 2011;17:4400–4413

29. Luo Q, Gu Y, Zheng W, et al. Erlotinib inhibits T-cell-mediated immune response via down-regulation of the c-Raf/ERK cascade and Akt signaling pathway. Toxicol Appl Pharmacol. 2011;251:130–6

30. Parsa AT, Waldron JS, Panner A, et al. Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med. 2007;13:84–88

31. Crane CA, Panner A, Murray JC, et al. PI(3) kinase is associated with a mechanism of immunoresistance in breast and prostate cancer. Oncogene. 2009;28:306–312

32. Marzec M, Zhang Q, Goradia A, et al. Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7-H1). Proc Natl Acad Sci U S A. 2008;105:20852–20857

33. Jiang X, Zhou J, Giobbie-Hurder A, Wargo J, Hodi FS. The activation of MAPK in melanoma cells resistant to BRAF inhibition promotes PD-L1 expression that is reversible by MEK and PI3K inhibition. Clin Cancer Res. 2013;19:598–609

34. Ghebeh H, Lehe C, Barhoush E, et al. Doxorubicin downregulates cell surface B7-H1 expression and upregulates its nuclear expression in breast cancer cells: role of B7-H1 as an anti-apoptotic molecule. Breast Cancer Res. 2010;12:R48

35. Zhang P, Su DM, Liang M, Fu J. Chemopreventive agents induce programmed death-1-ligand 1 (PD-L1) surface expression in breast cancer cells and promote PD-L1-mediated T cell apoptosis. Mol Immunol. 2008;45:1470–1476

36. Brahmer JR. Harnessing the immune system for the treatment of non-small-cell lung cancer. J Clin Oncol. 2013;31:1021–1028

37. Nemunaitis J, Nemunaitis M, Senzer N, et al. Phase II trial of Belagenpumatucel-L, a TGF-beta2 antisense gene modified allogeneic tumor vaccine in advanced non small cell lung cancer (NSCLC) patients. Cancer Gene Ther. 2009;16:620–624

38. Sienel W, Varwerk C, Linder A, et al. Melanoma associated antigen (MAGE)-A3 expression in Stages I and II non-small cell lung cancer: results of a multi-center study. Eur J Cardiothorac Surg. 2004;25:131–134

39. Butts C, Murray N, Maksymiuk A, et al. Randomized phase IIB trial of BLP25 liposome vaccine in stage IIIB and IV non-small-cell lung cancer. J Clin Oncol. 2005;23:6674–6681

40. Ramlau R, Quoix E, Rolski J, et al. A phase II study of Tg4010 (Mva-Muc1-Il2) in association with chemotherapy in patients with stage III/IV Non-small cell lung cancer. J Thorac Oncol. 2008;3:735–744

41. Neninger Vinageras E, de la Torre A, Osorio Rodríguez M, et al. Phase II randomized controlled trial of an epidermal growth factor vaccine in advanced non-small-cell lung cancer. J Clin Oncol. 2008;26:1452–1458

42. Duraiswamy J, Kaluza KM, Freeman GJ, et al. Dual Blockade of PD-1 and CTLA-4 Combined with Tumor Vaccine Effectively Restores T Cell Rejection Function in Tumors. Cancer Research. doi:10.1158/0008-5472.CAN-12–4100

43. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369:122–133

44. Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30:2691–2697

45. Weber JS, Dummer R, de Pril V, Lebbé C, Hodi FSMDX010-20 Investigators. . Patterns of onset and resolution of immune-related adverse events of special interest with ipilimumab: detailed safety analysis from a phase 3 trial in patients with advanced melanoma. Cancer. 2013;119:1675–1682

46. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–723

47. Brahmer JR, Drake CG, Wollner I, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010;28:3167–3175

48. . Rizvi et al., 2013 ASCO Annual Meeting. J Clin Oncol. 2013;31(suppl; abstr 8072)

49. . Weber et al., 2013 ASCO Annual Meeting. J Clin Oncol. 2013;31(suppl; abstr 9011)

50. Suzuki K, Kachala SS, Kadota K, et al. Prognostic immune markers in non-small cell lung cancer. Clin Cancer Res. 2011;17:5247–5256

51. Dieu-Nosjean MC, Antoine M, Danel C, et al. Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures. J Clin Oncol. 2008;26:4410–4417

52. Al-Shibli KI, Donnem T, Al-Saad S, Persson M, Bremnes RM, Busund LT. Prognostic effect of epithelial and stromal lymphocyte infiltration in non-small cell lung cancer. Clin Cancer Res. 2008;14:5220–5227

53. Lee JC, Lee KM, Kim DW, Heo DS. Elevated TGF-beta1 secretion and down-modulation of NKG2D underlies impaired NK cytotoxicity in cancer patients. J Immunol. 2004;172:7335–7340

54. Nagata S. Fas ligand and immune evasion. Nat Med. 1996;2:1306–1307

55. Drake CG, Jaffee E, Pardoll DM. Mechanisms of immune evasion by tumors. Adv Immunol. 2006;90:51–81

56. Hanagiri T, Shigematsu Y, Shinohara S, et al. Clinical significance of expression of cancer/testis antigen and down-regulation of HLA class-I in patients with stage I non-small cell lung cancer. Anticancer Res. 2013;33:2123–2128

57. Petersen RP, Campa MJ, Sperlazza J, et al. Tumor infiltrating Foxp3+ regulatory T-cells are associated with recurrence in pathologic stage I NSCLC patients. Cancer. 2006;107:2866–2872

58. Woo EY, Yeh H, Chu CS, et al. Cutting edge: Regulatory T cells from lung cancer patients directly inhibit autologous T cell proliferation. J Immunol. 2002;168:4272–4276

59. Bremnes RM, Al-Shibli K, Donnem T, et al. The role of tumor-infiltrating immune cells and chronic inflammation at the tumor site on cancer development, progression, and prognosis: emphasis on non-small cell lung cancer. J Thorac Oncol. 2011;6:824–833

60. Karimi S, Mohammadi F, Porabdollah M, Mohajerani SA, Khodadad K, Nadji SA. Characterization of melanoma-associated antigen-a genes family differential expression in non-small-cell lung cancers. Clin Lung Cancer. 2012;13:214–219

61. Kim SH, Lee S, Lee CH, et al. Expression of cancer-testis antigens MAGE-A3/6 and NY-ESO-1 in non-small-cell lung carcinomas and their relationship with immune cell infiltration. Lung. 2009;187:401–411

62. Guy CS, Vignali KM, Temirov J, et al. Distinct TCR signaling pathways drive proliferation and cytokine production in T cells. Nat Immunol. 2013;14:262–270

63. Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol. 2013;13:227–242

64. Rudd CE, Taylor A, Schneider H. CD28 and CTLA-4 coreceptor expression and signal transduction. Immunol Rev. 2009;229:12–26

65. Riley JL. PD-1 signaling in primary T cells. Immunol Rev. 2009;229:114–125

66. Patsoukis N, Brown J, Petkova V, Liu F, Li L, Boussiotis VA. Selective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation. Sci Signal. 2012;5:ra46

Copyright © 2014 by the European Lung Cancer Conference and the International Association for the Study of Lung Cancer.


Article Tools



Other Ways to Connect



Visit on your smartphone. Scan this code (QR reader app required) with your phone and be taken directly to the site.

 For additional oncology content, visit LWW Oncology Journals on Facebook.